Kleine-Levin Syndrome (KLS)

What is Kleine-Levin Syndrome (KLS) / Sleeping Beauty Syndrome?

Kleine-Levin Syndrome (KLS), also known as "Sleeping Beauty Syndrome", is a rare and complex neurological disorder that is characterized by periods of excessive sleep (hypersomnia; up to 20 hours a day), altered behaviour, mood swings and cognitive impairment. This syndrome is named after Willi Kleine and Max Levin, who were the first to describe cases of the disease in the early 20^th century. Multiple cases of recurrent hypersomnia were first collected and reported in Frankfurt by Kleine, while Levin emphasized the association of periodic somnolence with morbid hunger.

• KLS usually strikes adolescents, but can also occur in children as well as adults. Many patients can experience increased hunger (hyperphagia) as well as heightened sexual desire (hypersexuality).
• Generally speaking, each episodic attack can last for weeks or even months.
• During this period, patients exhibit excessive and abnormal sleep (hypersomnolence), waking only to eat and use the toilet.
• Onset of KLS is usually abrupt, often accompanied by flu-like symptoms. During these episodes, all daily activities stop completely. The patients are unable to care for themselves, perform normal tasks or go to school or office.
• KLS can occur for as long as a decade, with about 20 episodes occurring within this period of time.

Therefore, the disease is devastating for the patient not only at the personal level, but also at the professional and societal levels. In between these episodes, the patient is absolutely normal as if nothing had happened and is both mentally and physically in sound health. Of note is the fact that the patient cannot remember anything from the episode.

Epidemiology of Kleine-Levin Syndrome

KLS is an extremely rare disease and the exact prevalence is not known. It has been predicted that KLS possibly affects one in a million people. A systematic review of the published literature spanning from 1962 to 2004 by Arnulf et al. (2005) found only 186 cases of KLS worldwide, underscoring the rarity of the disease. Majority of the cases were from western countries. About one-sixth of patients were of Jewish descent, indicating that consanguinity (widely practised among the Jewish community) could play a role as a genetic cause of KLS. The disease affects men more frequently than females (sex ratio: 2:1).

What are the Causes of Kleine-Levin Syndrome?

KLS is classified based upon the underlying cause. For example, it is said to be primary if only hypersomnia is present, or secondary, if there are additional behavioral problems.

It has been suggested that KLS could be precipitated by a number of factors. These include winter season, brain infections, traumatic brain injury, alcohol consumption, marijuana use, sleep deprivation, stress, and physical exertion.

The exact cause of KLS is still not known. However, some proposals have been put forward in a bid to explain the pathogenesis of KLS:

• Thalamic & Hypothalamic Dysfunction: It is established that the thalamus and hypothalamus of the brain play a critical role in sleep, appetite, and body temperature regulation. However, there is no concrete evidence that KLS occurs due to dysfunction of the thalamus or hypothalamus. This is supported by the fact that brain imaging, cerebrospinal fluid (CSF) analysis and efforts to identify inflammatory markers have all yielded negative results.
• Kl�ver-Bucy Syndrome: This syndrome occurs due to damage to the medio-temporal lobes on both sides (bilateral lesions) of the brain. This also includes the amygdala, which is responsible for such behaviors as binge eating and hypersexuality.
• Hypoperfusion of the Diencephalon : The diencephalon is the posterior part of the forebrain. It includes the thalamus and its associated structures, as well as the third ventricle. Hypoperfusion of these areas of the diencephalon supports the diencephalic hypothesis and explains the clinical symptoms of KLS.

• Viral Infections: Post-mortem neuropathological investigations have found inflammatory lesions in the thalamus, diencephalon, and midbrain, suggesting that viral infections could be a cause of KLS. Some viruses that are incriminated include Epstein-Barr virus, varicella zoster virus, herpes zoster virus, influenza A virus, and adenoviruses.
• Neurotransmitter Imbalance: Abnormalities in serotonin and dopamine metabolism have been reported, suggesting that a neurotransmitter imbalance in the serotonergic or dopaminergic pathway could be a cause of KLS.
• Genetic Factor: Some researchers have found an increased frequency of the human leukocyte antigen (HLA) DQB1 * 0201 allele, indicating that KLS could be linked to a genetic cause. Moreover, it has also been observed that KLS can affect more than one individual in a family, suggesting a genetic link.

What are the Symptoms & Signs of Kleine-Levin Syndrome?

Common symptoms and signs of KLS include the following:

• Hypersomnia: This is characterized by excessive sleep, sometimes as long as 20 hours a day.
• Cognitive Impairment: This can be caused by frontal lobe syndrome in which the front portion of the brain is damaged. This is characterized by loss of motivation, planning and judgement abilities, accompanied by disorientation, hallucinations, including a loss of touch with reality.
• Hyperphagia: This includes periods of binge eating during an episode.
• Hypersexuality: This is characterized by an abnormally uninhibited sex drive.
• Mood & Behavioral Changes: The mood is usually depressed. It should be noted that this occurs as a consequence, and not as a cause, of the disorder. Sometimes, the patient exhibits childish behaviour.

How do you Diagnose Kleine-Levin Syndrome?

It should be noted that there could be a diagnostic delay of up to 4 years till an accurate diagnosis of KLS is made. This arises from overlapping of the symptoms with many psychiatric disorders. Therefore, the diagnosis is based upon a slow and painstaking process of exclusion. The doctor may perform the following tests to exclude other possible causes:

• Blood Tests: Simple blood tests can exclude conditions like diabetes, hypothyroidism, infections, inflammation, and autoimmunity.
• Lumbar Puncture: This is also known as a spinal tap, in which a needle is inserted into the spinal cavity in the lower back (technically termed as the lumbar region) to withdraw CSF. Analysis of the CSF can reveal any viral infections or other toxins that could have penetrated the brain.
• Brain Imaging: Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) can reveal any structural abnormalities in the brain, which could be indicative of a neurological disorder, including stroke and multiple sclerosis
• Electroencephalography (EEG):EEG investigation can be used to study sleep patterns and other brain abnormalities by measuring the electrical activity of the brain. The procedure uses leads that are attached to the surface of the scalp, which records electrical activity within the brain and produces a characteristic pattern on an electronic monitor. For example, in sleep studies, normal sleep patterns are characterized by "rapid eye movements" or REM sleep, with corresponding sleep waves that indicate a normal sound sleep. Any disturbance in these wave patterns is indicative of a hidden brain abnormality.

Diagnostic Criteria for Kleine-Levin Syndrome

In 1990, the diagnostic criteria for KLS were modified in the International Classification of Sleep Disorders (ICSD), where it has been defined as "a syndrome composed of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behavior" (ICSD 1990). This classification of the diagnostic criteria has greatly simplified the approach for the diagnosis of KLS.

Criteria A to E must be present to diagnose KLS

A. Two recurrent episodes of hypersomnia each lasting 2 days to 5 weeks

B. Episodes recur more than once a year or at least once every 18 months

C. Normal mood, alertness, cognition and behavior in between episodes

D. Presence of at least one of the following during the episode

• Cognitive impairment
• Altered perception
• Eating disorder
• Uninhibited behavior e.g. hypersexuality

E. No other underlying cause such as psychiatric disorder, drugs or medications found that might explain the symptoms

How do you Treat Kleine-Levin Syndrome?

• There is no definitive treatment for KLS. It is generally advised to "wait and watch" rather than going in for pharmacotherapy.
• Sometimes, antipsychotics like benzodiazepines, amphetamines, methylphenidate, and modafinil are used to treat sleepiness. However, these drugs can cause increased irritability and are not capable of improving cognitive impairment.
• Since KLS resembles with certain mood disorders like bipolar depression, lithium and carbamazepine are sometimes prescribed. These drugs have been shown to prevent further episodes in certain groups of patients.
• Sometimes, electroconvulsive therapy (ECT) is also recommended for treating depressive symptoms associated with KLS.

References:

1. What is KLS? � Kleine-Levin Syndrome Foundation - (https://klsfoundation.org/what-is-kleine-levin-syndrome/)
2. Kleine-Levin Syndrome Information Page � National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, USA - (https://www.ninds.nih.gov/disorders/all-disorders/kleine-levin-syndrome-information-page)

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